Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China.
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA.
Nat Rev Rheumatol. 2020 Oct;16(10):547-564. doi: 10.1038/s41584-020-0469-2. Epub 2020 Aug 17.
Regulated fibroblast growth factor (FGF) signalling is a prerequisite for the correct development and homeostasis of articular cartilage, as evidenced by the fact that aberrant FGF signalling contributes to the maldevelopment of joints and to the onset and progression of osteoarthritis. Of the four FGF receptors (FGFRs 1-4), FGFR1 and FGFR3 are strongly implicated in osteoarthritis, and FGFR1 antagonists, as well as agonists of FGFR3, have shown therapeutic efficacy in mouse models of spontaneous and surgically induced osteoarthritis. FGF18, a high affinity ligand for FGFR3, is the only FGF-based drug currently in clinical trials for osteoarthritis. This Review covers the latest advances in our understanding of the molecular mechanisms that regulate FGF signalling during normal joint development and in the pathogenesis of osteoarthritis. Strategies for FGF signalling-based treatment of osteoarthritis and for cartilage repair in animal models and clinical trials are also introduced. An improved understanding of FGF signalling from a structural biology perspective, and of its roles in skeletal development and diseases, could unlock new avenues for discovery of modulators of FGF signalling that can slow or stop the progression of osteoarthritis.
调控成纤维细胞生长因子（FGF）信号是关节软骨正常发育和稳态所必需的，这一点已被证实，因为异常的 FGF 信号会导致关节发育不良，并引发和促进骨关节炎的发生和进展。在四种 FGF 受体（FGFR1-4）中，FGFR1 和 FGFR3 与骨关节炎密切相关，FGFR1 拮抗剂以及 FGFR3 的激动剂在自发性和手术诱导的骨关节炎小鼠模型中显示出治疗效果。FGF18 是 FGFR3 的高亲和力配体，是目前唯一一种用于骨关节炎临床试验的基于 FGF 的药物。这篇综述涵盖了我们对调控正常关节发育和骨关节炎发病机制中 FGF 信号分子机制的最新理解。还介绍了基于 FGF 信号的骨关节炎治疗策略和动物模型及临床试验中的软骨修复策略。从结构生物学的角度更好地了解 FGF 信号及其在骨骼发育和疾病中的作用，可能会为发现能够减缓或阻止骨关节炎进展的 FGF 信号调节剂开辟新途径。
